Ion-strength independent sustained release pharmaceutical formulation

ABSTRACT

The present invention is related to an optionally coated pharmaceutical hydrophilic gel foaming matrix formulation comprising one or more active substances and having a prolonged release of said one or more active substances upon exposure to gastrointestinal fluids, characterized in that said release is substantially ion-strength independent. The invention is further related to a method of preparing this formulation which can be used in the administration of active substances for the treatment of a large number of disorders.

[0001] The present invention is related to a pharmaceutical formulation with a substantially sustained release behavior which is independent of the ion-strength of the dissolution medium, e.g. the gastrointestinal fluid. The sustained release is achieved over a time period up to 16 hours. The dosage form combines one or more active substances with a mixture of hydrophilic polymer carriers resulting in a gel forming matrix formulation.

[0002] Hydrophilic gel forming matrix formulations are well know dosage forms to control the dissolution behavior of active substances. The mechanism by which the active substance is released, starts with the hydration of the dosage form surface to form a gel structure. Simultaneously the active substance at the formulation surface dissolves in the dissolution medium. In the stationary phase, the dissolution medium continuously penetrates the gel structure and the gel expands. The active substance dissolves in the dissolution medium and is transported to the outer layer of the gel. Meanwhile, erosion of the outer layers of the gel occurs. Finally the release levels off, caused by the decreased concentration gradient of the active substance in the formulation and the penetrated dissolution medium. This mechanism is described in the prior art, e.g. Manford Robinson. The Theory and Practice of Industrial Pharmacy, 2^(nd) edition, Chapter 14: “Sustained Action Dosage Forms”.

[0003] Hydrophilic polymers used in the above described formulations are mostly polysaccharide carriers such as the cellulose derivates hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (NaCMC) or combinations of these cellulose derivatives.

[0004] Formulations of these type are described in numerous patents and patent applications, e.g. in U.S. Pat. No. 4,871,548 and EP-A-0923934.

[0005] U.S. Pat. No. 4,871,548 discloses a controlled release dosage form comprising an active compound and a mixture of at least a low viscosity cellulose ether and a high viscosity cellulose ether. EP-A-0923934 discloses a modified release matrix formulation of cefaclor and cephalexin comprising 5-35% of a mixture of hydrophilic polymers of different grades, wherein the hydrophilic polymers comprise about 0.1% to about 20% by weight of medium viscosity hydroxypropyl methylcellulose and about 0.1% to about 20% of low viscosity hydroxypropylcellulose

[0006] Although the above mentioned formulations are described as sustained release formulations in general, this sustained release only appears when the concentration of salts, the ion-strength, in the dissolution medium is low. The release rate of the active substance from the above mentioned formulation may be substantially dependent on the ion-strength. A high ion-strength may even lead to so-called dose-dumping. In this case the total amount of active substance is released in a very short time, which may lead to undesired, and even dangerous high blood levels of the active substance. A high ion-strength often occurs direct after taking a meal. As patients often take their medication just after a meal there is a high risk that ion-strength dependent formulations give rise to unwanted fast release of active substance instead of the desired sustained release.

[0007] WO 98/47491 describes a sustained release formulation wherein the control of the release of the active substance is based on a combination of two so called ‘intelligent’ polymers, having opposing wettability characteristics, one demonstrating a stronger tendency towards hydrophobicity and the other a stronger tendency towards hydrophilicity. In this formulation dose dumping can only be prevented by coating with an enteric coating.

[0008] It is the objective of the present invention to provide a sustained release formulation which is substantially independent from the ion-strength of the dissolution medium, which is normally the gastrointestinal fluid even when the formulation is not coated. It is obvious for a person skilled in the art that the formulation should also meet the normal physical and pharmaceutical requirements in the art, such as good flowing properties of the powder during tabletting, a crushing strength of compressed tablets of at least 30 N, a friability below 1% at a compression force between 10 and 40 KN, uniformity of content and sufficient stability. Further it is a requirement that the formulation can be prepared using normal formulation procedures and equipment, so that no large investments are necessary.

[0009] This objective can be achieved, according to the present invention, by a pharmaceutical hydrophilic gel forming matrix formulation having a prolonged release of one or more active substances upon exposure to gastrointestinal fluids, characterized in that said release is substantially ion-strength independent.

[0010] Prolonged release is defined as a (gradual) release of the active substance from the dosage form over a time period of 45 minutes or more. This period starts usually with the administration of the dosage form, or with the start of in-vitro dissolution test (the moment the dosage form is brought into the dissolution medium).

[0011] By the term substantially ion-strength independent is meant that the release rate profile of the active substance is not significantly changed (according to General Chapter 711: Physical tests and Determinations in USP 24 (±10% of label claim)) when the ion strength (I) is varied between 0.05 and 0.45 mol/l . The ion strength (I) is defined as I={fraction (1/2)}Σcz _(i) ², in which c is the concentration of the different ions in the solution and z_(i) their respective charge number (Handbook of Chemistry and Physics 71^(st) edition, David R. Lide ed., page 2-18, Boston, CRC Press Inc.; 1990-1991).

[0012] Although a coating is not essential to achieve the independency of the ion-strength, the formulation is optionally coated with a coating material in order to achieve another desired effect, such as masking of the taste or application of color. Suitable coating materials are known in the art and are for example HPMC, acrylics, ethylcellulose (see Graham Cole ed., Pharmaceutical Coating Technology, London, Taylor & Francis Ltd.; 1995)

[0013] The hydrophilic gel forming matrix has the form of tablets or of a multi-particulate dosage form and preferably contains a mixture of at lease two hydrophilic high viscosity cellulose ethers. Although the presence of a hydrophobic cellulose ether such as ethylcellulose will normally have no detrimental effect on the release properties of the present formulation, preferably no substantial amount of said hydrophobic cellulose ether is present. With a substantial amount of hydrophobic cellulose ether is meant an amount greater than 20% of the total weight of the gel forming polymers.

[0014] Cellulose ethers are well known in the art and are available in pharmaceutical grades and with different average molecular weights leading to different viscosities of a solution of these cellulose ethers. For the purpose of this patent application, hydrophilic polymers may be characterized by their viscosities in a 2% w/w aqueous solution as low viscosity (less than about 1000 mPas), medium viscosity (about 1000 mPas to about 10,000 mPas) and high viscosity (greater than about 10,000 mPas)

[0015] Hydrophilic hydroxypropyl methylcellulose polymers (HPMC's) which may be used in the present invention are available in different viscosity grades from Dow Chemical Co. under the brand name Methocel®) and from Shin Etsu under the brand name Metolose®.

[0016] Examples of low viscosity polymers are Methocel E5®, Methodcel E-15LV®, Methocel E50LV®, Methocel K100LV® and Methocel F50LV®, whose 2% aqueous solutions at 25° C. have viscosities of 5 mPas, 15 mpas, 50 mpas, 100 mPas and 50 mPas, respectively.

[0017] Examples of medium viscosity HPMC's are Methocel E4M® and Methocel K4M, whose 2% aqueous solutions at 25° C. have viscosities of 4000 mPas.

[0018] Examples of high viscosity HPMC's are Methocel K15M® and Methocel K100M® whose 2% aqueous solutions at 25° C. have viscosities of 15,000 mPas and 100,000 mpas.

[0019] Hydrophilic hydroxyethylcellulose polymers (HEC's) which may be used in the present invention are available in different viscosity grades from AQUALON under the brand name Natrosol® and from Amerchol Corporation under the brand name Cellosize®.

[0020] Examples of low viscosity polymers are Natrosol L® en Natrosol J®, whose 2% aqueous solutions at 25° C. have viscosities of 10 mPas and 20 mPas, respectively.

[0021] Examples of medium viscosity polymers are Natrosol G®) and Natrosol K® whose 2% aqueous solutions at 25° C. have viscosities of 200 mPas and 1500 mPas, respectively.

[0022] Examples of high viscosity polymers are Natrosol M® and Natrosol HH® whose 2% aqueous solutions have viscosities at 25° C. of 4000 mPas and 90000 mPas, respectively.

[0023] In a preferred embodiment of the present invention the formulation comprises a mixture of a high or medium viscosity hydroxypropylmethylcelluiose (HPMC) and a high or medium viscosity hydroxyethylcellulose (HEC). The ratio between the high or medium viscosity HPMC and the high or medium viscosity HEC is 1/0.85 to 1/1.2, preferably is 1/0.9 to 1/1.1, even more preferably is 1/0.95 to 1/1.05 and most preferred is 1/1. The formulation optionally may comprise a low viscosity HPMC. In that case the ratio between high or medium viscosity HPMC and low viscosity HPMC is in the range between 1/0.01 and 1/0.2 and preferably is between 110.01 and 1/0.1 and even more preferably is between 1/0.02 and 1/0.05.

[0024] It has surprisingly been found that formulations having the above mentioned composition can be used to prepare tablets that have a release rate that is independent of the ion-strength in the range that is normal in the gastro-intestinal fluid. Said normal range is between 0.17 and 0.35 mol/L.

[0025] Apart from its independence from the ion-strength, the release controlling principle of the formulation is also substantially independent from the pH in the range between pH=1.3 and pH=7.4. This means that the release rate of active substance is not influenced by the pH in those cases where the active substance release is not limited by the solubility of the active substance substance, i.e. that the differences in release values (in %) at a given point in time are less than 20% of the label claim (see Chapter Dissolution Specifications (page 1080-81) in FIP Guidelines for Dissolution Testing of Solid Oral Products (Final Draft, 1995), Drug Information Journal 1996, Vol 30, 1071-84) within the whole pH range between 1.3 and 7.4.

[0026] Because of its optimal properties as a sustained release formulation, the formulation according to the present invention can be used in the treatment of a large series of diseases in the case that sustained release properties are desirable. Examples of active substances that can be formulated into a sustained release formulation are active substances for the treatment of CNS disorders, including schizophrenia, episodic paroxysmal anxiety (EPA) disorders such as obsessive compulsive disorder (OCD), post traumatic stress disorder (PTSD), phobia and panic, major depressive disorder, bipolar disorder, Parkinson's disease, general anxiety disorder, autism, delirium, multiple sclerosis, Alzheimer disease/dementia and other neurodegenerative diseases, severe mental retardation and dyskinesias, such as Huntington's disease or Gilles dela Tourett's syndrome, anorexia, bulimia, stroke, addiction/dependency/craving, sleep disorder, epilepsy, migraine; attention deficit/hyperactivity disorder (ADHD); cardiovascular diseases including heart failure, angina pectoris, arrhythmias, myocardial infarction, cardiac hypertrophy, hypotension, hypertension—e.g. essential hypertension, renal hypertension, or pulmonary hypertension, thrombosis, arteriosclerosis, cerebral vasospasm, subarachnoid hemorrhage, cerebral ischemia, cerebral infarction, peripheral vascular disease, Raynaud's disease, kidney disease—e.g. renal failure; dyslipidemias; obesity; emesis; gastrointestinal disorders including irritable bowel syndrom (IBS), inflammatory bowel disease (IBD), gastroesophagal reflux disease (GERD), motility disorders and conditions of delayed gastric emptying, such as postoperative or diabetic gastroparesis, and diabetes, ulcers—e.g. gastric ulcer; diarrhoea; other diseases including osteoporosis; gynecological disorders, inflammations; infections such as bacterial, fungal, protozoan and viral infections, particularly infections caused by HIV-1 or HIV-2; pain; cancers; chemotherapy induced injury; tumor invasion; immune disorders; urinary retention; asthma; allergies; arthritis; benign prostatic hypertrophy; endotoxin shock; sepsis; complication of diabetes mellitus.

[0027] Preferred active substances to be formulated are active substances that are used for the treatment of CNS disorders, such as fluvoxamine (5-methoxy-1-[4-(trifluoro-methyl)phenyl]-1-pentanone O-(2-aminoethyl)oxime) or flesinoxan ((+)-benzamide, N-[2-[4[(2R)-2,3-dihydro-2-(hydroxymethyl)-1,4-benzodioxin-5-y!]-1-piperazinyl]ethyl]-4-fluoro), for the treatment of cardiovascular disorders, such as tedisamil (N,N′-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo[3.3.1]-nonane) or propanolol or active substances that are used in the treatment of gynecological disorders e.g. in Hormone Replacement Therapy, such as dydrogesterone, estradiol or conjugated estrogens. The present invention is especially useful for the formulation of the active substance flesinoxan, especially as its monohydrochloride ((+)-benzamide, N-[2-[4-[(2R)-2,3-dihydro-2-(hydroxymethyl)-1,4-benzodioxin-5-yl]-1-piperazinyl]ethyl]-4-fluoro-monohydrochloride), described in EP0138280 and EP307061 and for tedisamil, preferably as its sequifumarate (N,N′-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo-[3.3.1]-nonane 1.5 hydrogenfumarate), described in EP 0550383.

[0028] The present invention also relates to a method of preparing a formulation as described above, characterized in that

[0029] (1) a core is compressed of a mixture comprising one or more active substances and a mixture of at least two hydrophilic high or medium viscosity cellulose ethers yielding a substantially ion-strength independent and prolonged substantially zero-order release of active substances; and

[0030] (2) the core is optionally coated.

[0031] The ingredients HPMC, HEC, active substance, pigment blend and glidant are mixed in a suitable mixer. This powder mixture is blended with sodium stearyl fumarate in a suitable mixer.

[0032] The active substance may be added in the form of a pregranulate to the powder mixture used to compress. Alternatively the powder mixture for tabletting may be produced by a mixing procedure that is followed by a (wet or dry) granulation process.

[0033] The mixture of ingredients is compressed into tablets with commercial available equipment (e.g. a Courtoy® R0) using flow regulating agents like colloidal silica and lubricating agents like talcum, sodium stearyl fumarate or magnesium stearate. The quantity of hydrophilic celluloses in the complete formulation ranges between 15% and 99.5%, while the amount of active substance ranges between 0.1% and 80%. The amount of flow regulating and lubricating agent is fixed to improve powder flow properties and to prevent sticking of powder to the dye walls or the punches. The amount of glidant is between 0.05% and 5% and is preferably about 0.2%. The amount of lubricant is between 0.05% and 5% and is preferably about 0.4%. For commercial reasons, the powder mixture may be coloured with between 0.1% and 10% pigment blend. Typical pigment blends are commercially available, e.g. from COLORCON® as Opadry.®

[0034] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

[0035] The following examples are only intended to further illustrate the invention, in more detail, and therefore these example are not deemed to restrict the scope of the invention in any way.

EXAMPLE 1 Preparation f an Ion-strength Independent Formulation EXAMPLE 1a General Procedure for the Preparation

[0036] First colloidal silica is passed through a sieve. Said sieve possesses preferably a screen between 0.40 mm and 0.595 mm. The active substance is mixed together with the hydrophilic celluloses, colloidal silica, pigment blend and if required mannitol in a suitable mixer. Said mixer is preferably a high shear mixer with the granulator in off position. The sodium stearyl fumarate is passed through a sieve. Said sieve possesses preferably a screen between 0.40 mm and 0.595 mm. The powder mixture is compressed into tablets with the desired dimensions. The compression equipment is preferably a rotary machine, like Korsch and Courtoy equipment. Optional, the tablets can be coated with water soluble celluloses or derivates of cellulose like ethylcellulose or acrylates based on aqueous suspensions or organic solvents. The coating process is preferably carried out in perforated drum equipment or with equipment based on fluidized bed technology. TABLE 1 The composition of non-coated tablets (cores) , expressed in mg/tablet. Tedisamil Aceta- Fluvoxamine Tedisamil. sesqui Flesinoxan minophen maleate di HCl fumarate Label Label Label Label Label claim: claim claim: claim: claim: Materials 2 mg/t 2.2 mg/t 100 mg/t 100 mg/t 150 mg/t Flesinoxan.HCI 2.18 n.a. n.a. n.a. n.a. Acetaminophene n.a 2.19 n.a. n.a. n.a. Fluvoxamine maleate n.a. n.a. 100.00 n.a. n.a. Tedisamil.diHCl n.a. n.a. n.a. 124.4 n.a. Tedisamil.sesqui fum. n.a. n.a. n.a. n.a. 240.0 HPMC K4M 69.63 69.63 17.00 125.2 81.0 HPMC ES 7.50 7.50 12.50 20.0 14.0 HEC HX250PH 69.63 69.63 17.00 125.2 81.0 Mannitol SD200 n.a. n.a. 100.00 n.a. n.a. Colloidal silica 0.30 0.30 0.50 1.60 4.0 Pigment blend PB23015 0.15 0.15 n.a. 0.40 n.a. Sodium stearyl fumarate 0.60 0.60 3.00 3.20 5.0 Total tablet weight (mg) 150.00 150.00 250.00 400.00 425.00

[0037] TABLE 2 Properties of several compositions Fluvoxamine Tedisamil. Tedisamil maleat diHCl s squi Flesinoxan Acetaminophen Label claim: Label fumarate Label claim: Label claim 100 mg/t claim: 100 Label claim: Tablet property 2 mg/t 2.2 mg/t Coated mg/t 150 mg/t Tablet dimension 5.5 × 11.0 7.0 mm 8.0 mm 8.0 × 15.0 8.0 × 15.0 (mm) mm round round mm mm Special oblong oblong shaped Tablet weight (mg) 150 150 275  400  425 Crushing strength  83  75 144   71   90 (N) Friability (%) not not not  0.4 0.05 determined determined determined Release profile Table 4 Table 4 Table 4 Table 4 Table 4

Example 1b Release Properties of Several Formulations

[0038] The release of the active substance from the hydrophilic matrix tablets is measured in the USP apparatus If using paddles rotating at 50 rpm in either an USP dissolution buffer medium pH 6.8 of 0.05 molar (M), 0.17 M and 0.34 M prepared from di sodium hydrogen phosphate.2aq and citric acid.1aq (coded as F, G and H respectively) or in a half-change dissolution medium prepared from 0.1 M aqueous hydro chloride solution in the first part of the test (90 minutes) followed by 0.2 M pH 6.8 by adjusting with tri sodium phosphate.12 aq in the second part of the test. To increase the ionic strength of the aqueous solution during the test, sodium chloride is added to the solution. 1 liter dissolution medium of part two contains an amount of sodium chloride of respectively 0 gram (dissolution medium A), 10 gram (dissolution medium B), 15 gram (dissolution medium C), 30 gram (dissolution medium D1 and D2), and 50 gram (dissolution medium E1 and E2). In the dissolution media B, C, D1 and E1 the sodium chloride is only added in the second part of the test. In the dissolution media D2 and E275% of the sodium chloride is added in the first part of the test and 25% in the second part. The release of the active substance is measured over 16 hours with sample intervals of one hour during the first two hours followed by sample intervals of two hours over the remaining test period. Samples may be analysed on-line with a HPLC system or by UV spectroscopy. The release of the different active compounds from the formrulation is given in the tables 4a-4c.

[0039] From the release data as given in the tables 4a-4c is can be concluded that the release of active substance from the formulation according to the present invention is substantially independent from the pH and the ion-strength, as differences in release values are less than 20%. Further it can be concluded that there is no substantial difference between the release profile when the ion-strength is increased at low pH (pH 1.2) and at higher pH (pH 6.8) TABLE 3 Overview of dissolution media Dissolution medium Dissolution method A B C D1 D2 E1 E2 1) pH 1.2 1.5 hours 750 ml 0.1 HCI NaCl 22.5 37.5 added (g) 2) pH 6.8 14.5 hours 250 ml 0.2 M Na₃PO₄.12aq NaCl 0 10 15 30 7.5 50 12.5 added (g) Ion Strength (mol/L) 0.14 0.31 0.40 0.65 0.65 1.00 1.00 in final dissolution medium Dissolution medium Dissolution method F G H pH 6.8 Na₂HPO₄.2 aq + 0.05 M 0.17 M 0.34 M citric acid.1aq Ion Strength (mol/L) 0.11 0.38 0.77

[0040] TABLE 4a Release of several non-coated tablet compositions as function of time Amount of active sutstance (%) Flesinoxan Acetaminophen Fluvoxamine maleate Released after Label claim: 2 mg/t Label claim 2.2 mg/t Label claim: 100 mg/t Dissolution medium A B D1 E1 F G H A B C  0 hours 0 0 0 0 0 0 0 0 0 0  1 hour 20 18 20 18 21 15 25 22 22 22  2 hours 32 28 31 30 34 29 38 36 36 35  6 hours 59 52 53 50 70 63 70 67 66 64  16 hours 91 84 83 79 107 105 103 99 99 99

[0041] TABLE 4b Release f several non-coated tablet compositions as function of time Amount of active substance (%) Tedisamil.di HCl Tedisamil sesqul fumarate Released after Label claim: 100 mg/t Label claim 150 mg/t Dissolution medium A B C A D1 D2 E1 E2  0 hours 0 0 0 2 0 0 2 0  1 hour 32 32 33 20 18 20 20 21  2 hours 50 51 52 32 24 32 32 33  6 hours 84 85 84 47 45 49 47 52 16 hours 92 94 93 79 75 76 75 81

[0042] TABLE 4c Release of tedisamil sesqui fumarate non-coated tablet in one single dissolution medium as function of time Amount of active Tedisamil.sesqui fumarate substance (%) Label claim: 150 mg/t Released after 750 ml 0.1 M HCl + 250 ml Dissolution 750 ml 0.1 M HCl 0.2 M Na₃PO₄ · 12 aq medium (pH 1.2) (pH 6.8)  0 hours 0 0  1 hour 20 13  2 hours 33 22  6 hours 64 48 16 hours 97 89 

1. A pharmaceutical hydrophilic gel forming matrix formulation comprising one or more active substances and having a prolonged release of said one or more active substances upon exposure to gastrointestinal fluids, characterized in that said release is substantially ion-strength independent.
 2. A formulation according to claim 1, characterized in that said formulation is coated.
 3. A formulation according to claims 1-2, characterized in that said hydrophilic gel forming matrix comprises as a carrier a mixture of a least two hydrophilic high or medium viscosity cellulose ethers.
 4. A formulation according to claim 3, characterized in that said pharmaceutical formulation comprises high or medium viscosity hydroxypropylmethylcellulose (HPMC) and a high or medium viscosity hydroxyethylcellulose (HEC), in a ratio HPMC/HEC=110.85-11.2_and optionally a low viscosity HPMC in a ratio high or medium viscosity HPMC/low viscosity HPMC=1/0.01-110.2.
 5. A formulation according to claims 1-4, characterized in that said one or more active substances are selected from the group consisting of active substances for the treatment of CNS disorders, including schizophrenia, episodic paroxysmal anxiety (EPA) disorders such as obsessive compulsive disorder (OCD), post traumatic stress disorder (PTSD), phobia and panic, major depressive disorder, bipolar disorder, Parkinson's disease, general anxiety disorder, autism, delirium, multiple sclerosis, Alzheimer disease/dementia and other neurodegenerative diseases, severe mental retardation and dyskinesias, such as Huntington's disease or Gilles dela Tourett's syndrome, anorexia, bulimia, stroke, addiction/dependency/craving, sleep disorder, epilepsy, migraine; attention deficit/hyperactivity disorder (ADHD); cardiovascular diseases including heart failure, angina pectoris, arrhythmias, myocardial infarction, cardiac hypertrophy, hypotension, hypertension—e.g. essential hypertension, renal hypertension, or pulmonary hypertension, thrombosis, arteriosclerosis, cerebral vasospasm, subarachnoid hemorrhage, cerebral ischemia, cerebral infarction, peripheral vascular disease, Raynaud's disease, kidney disease—e.g. renal failure; dyslipidemias; obesity; emesis; gastrointestinal disorders including irritable bowel syndrom (IBS), inflammatory bowel disease (IBD), gastroesophagal reflux disease (GERD), motility disorders and conditions of delayed gastric emptying, such as postoperative or diabetic gastroparesis, and diabetes, ulcers-e.g. gastric ulcer; diarrhoea; other diseases including gynecological disorders, osteoporosis; inflammations; infections such as bacterial fungal, protozoan and viral infections, particularly infections caused by HIV-1 or HIV-2; pain; cancers; chemotherapy induced injury; tumor invasion immune disorders; urinary retention; asthma; allergies; arthritis; benign prostatic hypertrophy; endotoxin shock; sepsis; complication of diabetes mellitus.
 6. A formulation according to claim 5, characterized in that said active substance is an active substance for the treatment of CNS disorders.
 7. A formulation according to claim 6, characterized in that said active substance is fluvoxamine or flesinoxan or a pharmaceutically acceptable salt thereof.
 8. A formulation according to claim 7, characterized in that said active substance is flesinoxan monohydrochioride ((+>benzamide, N-[2-[4-[(2R)-2,3-dihydro-2-(hydroxymethyl)-1,4-benzodioxin-5-yl]-1-piperazinyl]ethyl]-4-fluoro monohydrochloride).
 9. A formulation according to claim 5, characterized in that said active substance is an active substance for the treatment of cardiovascular disorders.
 10. A formulation according to claim 9, characterized in that said active substance is tedisamil or propranolol or a pharmaceutically acceptable salt thereof.
 11. A formulation according to claim 10, characterized in that said active substance is tedisamil sesquifumarate (N,N′-dicyclopropylmethy-9,9-tetramethylene-3,7-diazabicyclo[3.3.1]nonane 1.5 hydrogenfumarate.)
 12. A formulation according to claim 5, characterized in that said active substance is an active substance in Hormone Replacement Therapy.
 13. A formulation according to claim 12, characterized in that said active substance is dydrogesterone, estradiol or conjugated estrogens.
 14. A method of preparing a formulation according to claim 1-13, characterized in that (1) a core is compressed of a mixture comprising one or more active substances and a mixture of at least two hydrophilic high or medium viscosity cellulose ethers yielding a substantially ion-strength independent and prolonged substantially zero-order release of active substances; and (2) the core is optionally coated. 